The natural (or innate) immunity of man to Trypanosoma brucei, a trypanosome morphologically indistinguishable from the human pathogen T. rhodesiense, may be related to the presence of a cytotoxic factor in normal human serum. The trypanocidal activity of normal human serum has recently been found to be associated with purified human high density lipoprotein (HDL). I propose to study the interaction of HDL with trypanosomes with two main objectives: 1) Elucidation of those chemical properties of HDL which are necessary for and confer specificity to the trypanocidal activity. This will involve: a) comparison of the lipid composition of 'active' HDL derived from human or baboon serum and 'inactive' HDL derived from rat or rabbit serum; b) modification of the proteins or lipids of HDL followed by analysis of changes in trypanocidal activity. 2) Investigation of the cellular basis for the differential effect of human HDL on T. brucei and T. rhodesiense blood forms. This will necessitate a) isolation of plasma membrane fractions of these trypanosomes for biochemical analysis; b) analysis of the effect of HDL on plasma membrane lipids; c) studies of lipid metabolism of these trypanosomes maintained in vitro. Elucidation of the biochemical and cellular basis for the specific interaction of HDL with trypanosomes will contribute to a better understanding of the factors which may mediate host range specificity of trypanosomes of the brucei-subgroup. Interaction between host HDL and trypanosomes may also point to an important metabolic relationship which might be exploited in devising a rational approach to chemotherapy of trypanosomiasis.